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Nihms 1625910
Nihms 1625910
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Clin Sci (Lond). Author manuscript; available in PMC 2020 September 09.
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Abstract
Nintedanib, a FDA -approved drug for the treatment of patients with idiopathic pulmonary
fibrosis, inhibits both tyrosine kinase receptors and non-receptor kinases, and block activation of
platelet-derived growth factor receptors, fibroblast growth factor receptor, vascular endothelial
growth factor receptors and Src family kinases. Preclinical and clinical studies have revealed the
potent anti-fibrotic effect of nintedanib in idiopathic pulmonary fibrosis in human and animal
models. Recent preclinical studies have also demonstrated the inhibitory effect of nintedanib on
the development and progression of tissue fibrosis in other organs, including liver, kidney, and
skin. The anti-fibrotic actions of nintedanib occur through a number of mechanisms, including
blocking differentiation of fibroblasts to myofibroblasts, inhibition of epithelial-mesenchymal
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transition, and suppression of inflammation and angiogenesis. In this article, we summarize the
mechanisms and efficacy of nintedanib in the treatment of fibrotic diseases in animal models and
clinical trials, provide an update on recent advances in the development of other novel antifibrotic
agents in preclinical and clinical study, and offer our perspective about the possible clinical
application of these agents in fibrotic diseases.
Keywords
Receptor tyrosine kinases; Src; Nintedanib; Antifibrotic agent; Fibrotic disease
Introduction
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Nearly 45% of deaths in the developed world are attributable to some type of chronic fibro-
proliferative disease, including idiopathic pulmonary fibrosis (IPF)[1], liver, kidney and
cardiac fibrosis, that lead to organ dysfunction and failure [2]. Until recently, there have been
*
Correspondence: Shougang Zhuang, MD, PhD, Alpert Medical School of Brown University, Rhode Island Hospital -Middle House
301, 593 Eddy Street, Providence, RI 02903, szhuang@lifespan.org.
Author Contributions
Feng Liu designed and wrote the manuscript; George Bayliss edited the manuscript; and Shougang Zhuang designed and edited the
manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
Liu et al. Page 2
and morbidity rates, despite decades of research that have identified numerous potential
targets to counter fibrosis in different organs [2]. Recent clinical trials have demonstrated
that the receptor tyrosine kinases (RTKs) inhibitor nintedanib demonstrates a powerful anti-
fibrotic effect in idiopathic pulmonary fibrosis (IPF), leading to its 2014 approval by the
Food and Drug Administration (FDA) for treatment of IPF [3]. Inspired by this
breakthrough, researchers conducting preclinical studies have shown that nintedanib has
anti-fibrotic effects in other organs, including liver and kidney, and in systemic sclerosis.
Preclinical and clinical studies are also underway on the effects of other antifibrotic agents
[2]. This article reviews the use of nintedanib in treating IPF and non-pulmonary fibrotic
diseases and summarizes scientific efforts to develop other novel antifibrotic agents to treat
fibrotic diseases in humans (Table 1).
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Efforts to develop angiogenesis inhibitors for the treatment of cancer have been underway
for 20 years [5]; nintedanib ethanesulfonate, a 6-methoxycarbonyl-substituted indolinone
derivative identified during this time, has subsequently advanced to become a first-line
targeted therapy against tumors. Nintedanib (BIBF 1120) is a potent, indolinone-derived
small molecule, multiple-receptor TKI, that simultaneously blocks the intracellular ATP-
binding pocket of RTKs, resulting in inhibition of the phosphorylation of specific tyrosine
kinases, including PDFGR-α, PDFGR-β, FGFR-1, 2, 3, VEGFR-1, 2, VEGFR-3 and Src
family kinases (Src, Lyn and Lck)[4]. As a first-line targeted cancer therapy, nintedanib has
been shown to regulate tumor cell proliferation, differentiation, apoptosis, metastasis and
angiogenesis, and has demonstrated broad clinical application in treating lung carcinoma,
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RTKs as well as Src family kinases have all been implicated in fibrosis. Many TKIs that
block specific RTKs have also demonstrated anti-fibrotic effects [4]. Researchers have come
to regard combined inhibition of different profibrotic mediators as a promising approach for
the treatment of fibrosis [11].Therefore, the broader spectrum of nintedanib-elicited
inhibition of profibrotic signaling molecules distinguishes it from other single-receptor
kinase inhibitors since nintedanib may offer additive effects with few side effects as
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compared with selective inhibition of individual profibrotic molecules. In the past decade, a
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number of preclinical studies and clinical trials have confirmed its antifibrotic effects in IPF
through inhibition of pulmonary fibroblast activation, epithelial–mesenchymal transition
(EMT), inflammatory cell infiltration, angiogenesis and TGF-β-induced fibrotic events [12–
16]. In primary human lung fibroblasts from patients with IPF (IPF-HLF), nintedanib
inhibited PDGF- and FGF-stimulated fibroblast motility in a concentration-dependent
manner [12]. Nintedanib also inhibited TGF-β-induced fibroblast to myofibroblast
transformation in primary human lung fibroblasts from IPF patients [13], while somewhat
controversial results demonstrated that nintedanib at concentrations of ⩾300 nmol·L−1 did
not change the morphology of primary alveolar type II epithelial cells derived from donors
without IPF and showed no inhibitory activity on the TGF-β-induced EMT at 2 ng/mL [16].
Nintedanib reduced TGF-β-stimulated collagen secretion and deposition by primary human
lung fibroblasts from patients with IPF cultured for 48 h and reduced secreted TIMP-2 levels
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The first clinical evidence for the efficacy of nintedanib in patients with IPF came from the
TOMORROW trial, a multi-national, double-blinded, randomised, placebo-controlled, 52-
week, phase II clinical trial [23]. In this study, researchers demonstrated that treatment with
a 150-mg dose of nintedanib twice a day showed a promising numerical trend toward a
reduction in the annual rate of decline in forced vital capacity (FVC) by approximately 68%.
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Nintedanib also reduced the incidence of acute exacerbations and improved the quality of
life [23]. After completion of the 52-week period (period 1), patients could continue with
nintedanib treatment for a further blinded period (period 2). The effect of nintedanib on
slowing IPF progression persisted up to week 76.
The INPULSIS trials, two double-blind, randomized, placebo-controlled, 52-week, phase III
clinical trials (INPULSIS-1 and INPULSIS-2)[19], enrolled 1061 patients from 24 countries
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and demonstrated that nintedanib significantly reduced the annual rate of decline in FVC.
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The researchers further showed that the beneficial effects of nintedanib were consistent
irrespective of sex, age and race, and by FVC based on the 70% threshold [24, 25]. Some
734 patients out of 807 who completed the INPULSIS trials continued to be followed in
INPULSIS-ON (430 continuing nintedanib, 304 initiating nintedanib). An interim analysis
of a data snapshot in October 2016 suggests that the efficacy of nintedanib in slowing
respiratory function decline persists beyond 144 weeks. The adjusted annual rates of decline
in FVC of these patients during the 144-week period were similar to the decline in
nintedanib recipients in the INPULSIS trials. The mean total exposure for patients treated
with nintedanib in both INPULSIS and INPULSIS-ON was 40.7 months, with a maximum
exposure of 63.1 months. Analyses of pooled data from two replicate phase III INPULSIS
trials examining the effects on nintedanib on baseline FVC % predicted ≤90% or >90%
showed that patients with IPF and preserved lung volume (FVC >90% predicted) have the
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same rate of FVC decline and gain the same benefit from nintedanib as patients with more
impaired lung volume (baseline FVC ≤90% predicted)[25]. This also underscores the
importance of prompt diagnosis of IPF to enable patients to receive nintedanib treatment as
soon as possible and for as long as possible to obtain beneficial effects over the long term.
These results suggest that nintedanib is effective in reducing the decline in FVC at least up
to 3 years [22] and in improving the quality of life of patients with end stage of IPF [26].
Acute IPF exacerbations are associated with significantly increased morbidity and mortality.
The TOMORROW and INPULSIS trials provided mixed results regarding the effect of
nintedanib on acute exacerbations. Nintedanib significantly increased the time to the first
acute exacerbation in INPULSIS-2, and reduced the incidence of acute exacerbations in
TOMORROW [22].Treatment with nintedanib reduced the risk of experiencing a first
investigator-reported acute exacerbation by 47% [27]. Acute exacerbations reported as
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serious adverse events occurred in 3.6% patients in the nintedanib group vs. 6.1% in the
placebo group. The INPULSIS-ON trial also suggests that nintedanib is effective in reducing
the number of acute exacerbations at least up to 3 years. These two trials showed that
nintedanib reduces the risk of on-treatment mortality by 43% [27]. A recent post hoc
analysis of pooled INPULSIS data showed that a smaller percentage of nintedanib recipients
had a significant decline in FVC compared with placebo recipients.
Pirfenidone is another drug that has been approved for use in the treatment of IPF. In a real-
world clinical setting, patients with IPF who were not eligible for pirfenidone treatment
could be included in a compassionate use program for nintedanib [28]. Consistent with data
from the INPULSIS-2 and TOMORROW trials, nintedanib reduced IPF progression in the
majority of the patients who weren’t eligible for pirfenidone. After 6 months of nintedanib
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treatment, 63% of patients had a FVC decline of less than 5% from baseline [28].The
authors of the study noted that nintedanib treatment stabilized disease progression in 62% of
the patients who had not responded to pirfenidone in the previous 6 months [28].. These
clinical trials demonstrated the effectiveness of nintedanib in slowing disease progression,
and suggested that nintedanib treatment may ultimately reduce mortality in patients with IPF
with good tolerability and safety profiles [22]. The beneficial effects of nintedanib in IPF
patients are offset by adverse events and high cost. Some 50% of patients on the drug suffer
an adverse event, leading to treatment discontinuation in 5% to 15% (depending on existing
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studies)[29]. The cost per quality-adjusted life year (QALY) exceeds 140,000 USD for
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nintedanib. This seems prohibitive as compared to the classical willingness to pay threshold
of 50,000 USD per QALY under which an intervention is considered to be cost-effective
[29].
I. Liver Fibrosis
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TIMP1 induced by PDGF and TGF-β. Nintedanib also inhibited expression of periostin, a
TGF-β superfamily-responsive matricellular protein that is produced by fibroblasts and is
involved in collagen fibrillogenesis and ECM organization. Moreover, nintedanib inhibited
TGFβ1-stimulated integrin alpha 5 (ITGA5) expression in fibroblasts and promoted
fibroblast motility and survival [34]. In a human hepatic stellate cell line (LX2), nintedanib
significantly abrogated collagen I, TGF-β 1, TIMP1 and ITGA5 expression. All those results
indicated that nintedanib may inhibit resident liver cell activation, differentiation, migration
and contractility. In a CCl4-induced acute liver injury mouse model, nintedanib significantly
down-regulated expression of collagen I, fibronectin, periostin, ITGA5, TIMP1, α -SMA
and desmin (HSCs activation marker). Nintedanib administration also strongly attenuated
expression of major inflammatory cytokines such as TNFα (tumor necrosis factor alpha) and
CCL2 (C-C motif chemokine ligand 2), MCP1 (macrophage chemotactic protein) and IL-6
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In summary, nintedanib is able to attenuate liver fibroblast and HSC activation and suppress
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starting 3 days after UUO injury or folic acid injection. In cultured renal interstitial
fibroblasts, nintedanib also inhibited TGF-β1- or PDGF-BB-induced renal fibroblast
activation and ECM protein expression. Interestingly, delayed application of nintedanib not
only halted further deposition of ECM proteins, but also partially reduced their levels to
below what had been accumulated before treatment. This suggests that nintedanib is also
able to reverse established renal fibrosis in addition to attenuating development and
progression of renal fibrosis. These finding are consistent with other reports that late
treatment with nintedanib ameliorated fibrosis in animal models of lung and systemic
sclerosis [13, 37]. The mechanism may be in part associated with its regulation of the
imbalance between MMPs and TIMPs, which are involved in ECM metabolism [38].
Mechanistically, nintedanib can block activation of PDGFR, FGFR, VEGFR and Src family
kinases (Src, Lyn, Lck) induced by UUO injury. Src can directly induce EGFR
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phosphorylation and also induce EGFR transactivation through cleavage of EGFR legends,
releasing its soluble form [4]. Lck and Lyn kinase are proved to be involved in inflammation
and fibrogenesis. Nintedanib reduced macrophage infiltration and proinflammatory
cytokine/chemokine (i.e. MCP-1, TNF-α, IL-6, and IL-1β) production induced by UUO
injury. It also blocked phosphorylation of RTK downstream signaling proteins, such as
STAT3 and NF-κB in UUO-induced injuried kidneys. These signaling proteins play
important roles in the signal transduction associated with inflammatory responses and renal
fibrosis. Furthermore, nintedanib inhibits phosphorylation of Smad2/3, a key signaling
molecule mediating biological actions of TGF-β1. It may accomplish that by specifically
inhibiting tyrosine phosphorylation of the TGF-β1 receptor since phosphorylation of the five
tyrosine residues within the cytoplasmic tail of the type II TGFβ receptor (TβRII) is
indispensable for Smad-dependent fibrotic signaling in the kidney [39]. Collectively,
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nintedanib may protect against renal fibrosis through mechanisms associated with blockade
of multiple RTKs, Src family kinases, TGF-β activation and their downstream signaling
pathways involved in renal fibrogenesis.
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and animal models of SSc [37]. They found that nintedanib dose-dependently reduced
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induced skin fibrosis as well [37]. Furthermore, nintedanib can reduce clinically detectable
skin disease as evidenced by a reduced cGvHD score. In the murine Tight skin-1 (Tsk-1)
model, treatment with nintedanib reduced hypodermal thickening, myofibroblast counts and
hydroxyproline content of the skin [37].
Fos-related antigen-2 transgenic (Fra2 transgenic) mice display the core clinical fibrotic and
vascular manifestations of SSc [41]. Fra2 transgenic mice develop a destructive
microvascular disease with apoptosis of endothelial cells followed by systemic fibrotic
manifestations and PAH [41]. By utilizing this model, Huang et al verified the antifibrotic
and vasoprotective effects of nintedanib [42]. Nintedanib also decreased the number of
apoptotic endothelial cells in the skin and lungs and normalized the levels of M-CSF1 and
VEGF of Fra2 transgenic mice. Interestingly, nintedanib treatment completely prevented the
increase in M2 macrophages, but M1 macrophage counts were not affected [42]. These
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IV. Retinopathy
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but did not compromise the established vascular network during development. The
inhibitory effects of nintedanib on the oxygen-induced retinopathy (OIR) may be through
blocking phosphorylation of MAPK (Erk1/2) and AKT. Nintedanib exerted suppression of
OIR-induced expression of VEGF negative regulator Dll4, and repulsive factor EphrinB2
and its receptor EphB4, while attenuating the rise in VEGF and Netrin-1, resulting in
enhanced normal retinal vascularization. Therefore, when nintedanib is injected at early
stages of ROP, it can accelerate normal vascularization, which is essential to prevent pre-
retinal neovascularization and long-term functional damage [44]. These properties could be
of interest for the treatment of a variety of ischemic retinopathies associated with
pathological neovascularization in addition to ROP, notably diabetic retinopathy.
Neovascular age-related macular degeneration (AMD) is one of the most common eye
disorders that impair vision and is the leading cause of blindness in the elderly [45].
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Nintedanib added to a light-sensitive polymer injected into in the posterior segment of the
eye brown Norway rates was shown to inhibit angiogenesis significantly prior to laser
induction of choroidal neovascularization [45], suggesting a role for nintedanib and this
novel UV light-sensitive nanoparticle drug delivery system.
have value as potential therapies in other fibrotic diseases, also complimenting nintedanib..
I. Pirfenidone
Pirfenidone is an antifibrotic, anti-inflammatory and antioxidant compound that was recently
approved by the FDA for patients with IPF [20]. It inhibits production of TGF-α and free
radical oxygen species (ROSs), as well as reduces IL-1, IL-6, IL-8, IL-12 and TNF-α levels
[46]. Several preclinical studies and clinical trials have indicated that pirfenidone is effective
in in treating IPF and renal fibrosis [20, 47]. The first clinical study of pirfenidone for IPF –
a phase II, multicenter, randomized, double-blind trial – showed no significant therapeutic
effect on the primary endpoint of a change from baseline in the lowest oxygen saturation by
pulse oximetry [SpO2] during a 6-minute exercise test [48]. High-dose treatment (1800 mg/
day) had a positive effect in reducing VC decline, a secondary endpoint, at 9 months [48]. A
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subsequent multicenter, randomized, double-blind phase III clinical trial of 275 patients with
IPF randomly assigned to pirfenidone 1800 mg/day, pirfenidone 1200 mg/day, or placebo for
52 weeks, showed a significantly slower decline in FVC and better progression-free survival
in the two pirfenidone groups compared with placebo [46].The placebo-controlled phase III
CAPACITY 004 and 006 trials showed that the primary endpoint of a significant reduction
in FVC declines at week 72 was only met in study 004, which assigned patients in a 2:1:2
ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo [49]. In study 006, in
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which patients were assigned d in a 1:1 ratio to pirfenidone 2403 mg/day or placebo, the
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pirfenidone 2403 mg/day group had higher incidences of side-effects than the placebo
group. The pooled analysis, however, revealed a significant reduction in the mean decline of
absolute and percent predicted FVC; even patients with an FVC decline ≥10% at week 72 in
the 2403 mg/day pirfenidone group still had longer progression-free survival and a lower
rate of decline in mean 6-minute walk distance (6MWD) than patients in the placebo group
[49]. Finally, the ASCEND trial looked at 555 patients from the USA, Europe, and Australia
who were randomly assigned to receive 2403 mg/day of pirfenidone or placebo for 52 weeks
[50]. It, too, showed that the treatment group had a significantly reduced absolute decline in
FVC, fewer patients with an FVC decline ≥10%, better progression-free survival and fewer
patients with a decrease of ≥50 m in distance walked during the 6MWD [50]. The
CAPACITY and ASCEND trials showed a reduction in both all-cause and IPF-related
mortality after one year [50].
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Recent preclinical research has looked at the effect of pirfenidone on renal fibrosis. Rao et
al. showed that pirfenidone inhibited mesangial matrix expansion and reduced levels of type
I and IV collagen, and fibronectin gene expansion in kidneys of mice with diabetic
nephropathy (DN). They suggest that the mechanism of action may be through inhibition of
phosphorylation of eIF4E, thereby preventing mRNA processing and expression of fibrotic
proteins [51]. Using a 5/6 nephrectomy rat model Sharma et al. found that pirfenidone
inhibits M1 and M2 macrophage infiltration [52]. In UUO rats and cultured HK-2 cells,
pirfenidone significantly attenuated TGF-β1-induced EMT and ECM synthesis, as
determined by reducing expression of α-SMA, type I and III collagen, S100A4, fibronectin,
and increased expression of E-cadherin, along with inhibiting TGF-β1-induced up-
regulation of phosphorylation of ERK1/2, p38 and JNK [47]. Preclinical studies indicated a
significant effect of pirfenidone on renal fibrosis. The only human trial to date so far has
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been a RCT in 77 patients with DN. The trial showed that after 1 year of therapy with
pirfenidone, patients in the treatment arm with eGFR ranging from 20 mL/min/1.73 m2 to 75
mL/min/1.73 m2 experienced an average increase in eGFR of +8.5 mL/min/1.73 m2
compared with a mean eGFR decrease of 2.2 mL/min/1.73 m2 in the placebo group [52].
More experimental and clinical trials are needed to evaluate whether pirfenidone could be
used for clinical treatment of fibrotic renal diseases.
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patients with NASH before and after treatment with either rosiglitazone or pioglitazone for
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A possible role for non-TZD PPARγ agonists on fibrotic diseases has been looked at in pre-
clinical studies but in only limited clinic studies. Fenofibrate, a PPARα agonist, may prevent
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To date, there are only preclinical animal studies on the treatment of fibrotic diseases with
PPARβ/δ agonists [2]. It has been reported that GW0742, a synthetic agonist of PPARβ/δ,
prevented bleomycin-induced lung fibrosis, inflammation, pulmonary artery banding-
induced cardiac hypertrophy and fibrosis in mice [61]. GW0742 also reduced markers of
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cardiac fibrosis in a rat model of type-1 diabetes-associated cardiac fibrosis [62]. Another
PPARβ/δ agonist, GW610742, inhibited collagen deposition in a rat model of corneal
wounding [63]. The PPARβ/δ agonist GW501516 reduced peritoneal fibrosis and
inflammation in rats [64]. The PPARβ/δ agonist HPP593 may effectively abrogate renal
fibrosis induced by chronic ischemia, through reduction in oxidative stress and preservation
of mitochondrial function [65]. The PPARβ/δ agonist KD3010 has been reported to prevent
liver fibrosis induced by CCl4 or chronic cholestasis [66]. More recent studies indicated that
dual-, pan-, or mixed PPAR agonists have shown potential for treating fibrotic disease [2].
III. Pentoxifylline
Pentoxifylline, a methylxanthine derivative, has been approved recently for the treatment of
vascular diseases. Its main clinical properties include improving the rheological properties of
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blood, anti-inflammatory effects, and antioxidative effects [67]. Several preclinical studies
have shown an inhibitory effect of pentoxifylline on fibrotic diseases including radiation-
induced fibrosis, schistosomiasis-induced hepatic granulomas, chronic pulmonary
paracoccidioidomycosis, miscellaneous fibrotic conditions, peritoneal fibrosis and
tubulointerstitial fibrosis. Pentoxifylline is thought to act through downregulation of the
expression of TGF-β1 and reduction of proinflammatory and inflammatory factors [67].
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The effect of pentoxifylline on radiation-induced fibrosis was largely spurred by the known
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Pentoxifylline has been shown to be effective therapy for oral submucosal fibrosis. In a
randomized, placebo-controlled clinical trial, 14 of 29 patients in the study were orally
administered pentoxifylline (800 mg/day) for 1 month and then 1200 mg/day for the
subsequent 6 months. The treatment arm demonstrated significant improvement of
conditions associated with oral submucosal fibrosis, compared to the control group [71].
Similar results were observed in another randomized, placebo-controlled clinical trial
involving a larger series in which 32 of 62 patients received the active drug [72]. A separate
randomized, placebo-controlled clinical trial in which 106 patients were administered a
smaller dose of pentoxifylline (800 mg/day) orally for a shorter duration (3 months)
demonstrated significant improvement in all variables assessed, compared to the control
group [73]. It will be of interest to investigate the potential effect of pentoxifylline on oral
submucous fibrosis in other populations.
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Pentoxifylline may have a role as a therapeutic agent in CKD through its anti-inflammatory
and antiproteinuric properties. Perkins et al. documented slower progression of CKD in
patients who took pentoxifylline versus placebo for 1 year, with the PTF treatment group
showing an eGFR decline of −1.2 mL/min/1.73 m2 compared with −7.2 mL/min/1.73 m2 in
the control group [74]. A prospective RCT in 91 patients with eGFR <60 mL/min/1.73 m2
randomized to receive pentoxifylline or placebo, Goicoechea et al. found that serum CRP,
fibrinogen and TNF-α decreased significantly in the pentoxifylline group [75]. A single-
center retrospective analysis conducted by Chen et al examined the combination of
pentoxifylline with ACE inhibitors or ARBs in patients with advanced CKD. They found no
change in overall mortality or risk of incident cardiovascular events [76]. The patients with
the addition of pentoxifylline, however, had better renal outcomes, demonstrating a 40%
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lower risk of developing ESRD than treatment with an ACE inhibitor or ARB alone,
especially in patients with heavy proteinuria [76].
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with advanced CKD and type 2 diabetes at 24 weeks of follow-up [78]. A larger RCT, in
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which more than 2000 patients with stage 4 CKD and diabetes were randomized to receive
either bardoxolone methyl or placebo, failed to demonstrate a reduction in progression to
ESRD or death and was also associated with a higher rate of cardiovascular events in the
treatment arm [79]. In 2018, a post-hoc analysis of data from the Bardoxolone methyl
Evaluation in patients with CKD and type 2 diabetes study (BEACON) suggested that
bardoxolone methyl may preserve kidney function and delay the onset of ESRD in patients
with T2D and stage 4 CKD. Conducted as a multinational, randomized, double-blind,
placebo-controlled phase 3 trial, BEACON enrolled around 2,600 patients with T2D and
CKD stage 4 [80]. Patients randomized to bardoxolone methyl experienced mean increases
in eGFR that were sustained through study week 48 while increases in eGFR from baseline
were sustained 4 weeks after cessation of treatment[80]. These patients were significantly
less likely to experience the composite renal endpoint.
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including nintedanib, show great promise in slowing down and even reversing fibrosis,
translating that knowledge into effective antifibrotic therapies in humans has been limited
due to lack of sufficient effects, off-target effects or both. As such, more clinical trials of
nintedanib in other chronic fibrotic disease are warrantied.
Researchers are also encouraged by recent preclinical studies and clinical trials
demonstrating the effectiveness, safety and tolerability of other novel antifibrotic agents
such as perfenidone, PPARs agonist, pentoxifylline and bardoxolone methyl in slowing
progression or even reversing renal fibrosis. But more clinical studies, in particular, large
randomized-controlled clinical trials, are necessary to evaluate whether these promising
antifibrotic agents will translate into actual therapies against chronic fibrotic diseases.
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Acknowledgements
This work was supported by the grants from Economic Commission of Pudong New District of Shanghai
(PKJ2017-Y19 to L.F.), the National Nature Science Foundation of China (81470920, 81670623, and 81830021 to
S.Z) and the Branch grant of National key grants of Ministry of Science and Technology (2018YFA0108802 to
S.Z.).
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Liu et al. Page 13
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Table1.
Cultured 3T3 fibroblasts and primary human liver Attenuates liver fibroblasts and HSC activation, collagen 33
hepatic stellate cells; CCl4-induced liver deposition, HSC differentiation, contractility and migration,
fibrogenesis in a mouse model intrahepatic inflammation and angiogenesis
Cultured renal interstitial fibroblasts; UUO and kidney Inhibits renal fibroblasts activation, ECM overproduction and 36
folic acid injection induced renal fibrosis mouse deposition, inflammatory cells infiltration and TGF-β-induced
models fibrotic events, may attenuate pre-established renal fibrosis
Dermal fibroblasts from patients with SSc; mouse skin Reduces PDGF-induced and TGF-β-induced dermal fibroblasts 37,42
model of bleomycin-induced skin fibrosis; model proliferation and migration, EMT and collagen release;
of murine sclerodermatous chronic graft-versus- attenuates dermal thickening, myofibroblast counts and
host disease (cGvHD); murine Tight skin-1 hydroxyproline content of the skin, inflammatory cells
(Tsk-1) model; Fos-related antigen-2 transgenic infiltration ;regresses pre-established dermal fibrosis;
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Vasoobliteration model; rodent model of eye Interferes with retinal angiogenesis, retinal vaso-obliteration, 43,44
neovascular age-related macular degeneration reduces pathological neovascularization and promoted retinal
vascularization; inhibits laser-induced choroidal
neovascularization
IPF: idiopathic pulmonary fibrosis; ECM: extra matrix; TGF: transforming growth factor; HSC: hepatic stellate cells; EMT: epithelial-
mesenchymal transition; UUO: unilateral ureteral obstruction; SS: systemic sclerosis; PDGF: platelet-derived growth factor
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